南方医科大学第八附属医院（佛山市顺德区第一人民医院）

The Midasin AAA (ATPase associated with various activities) ATPase 1 (MDN1) gene, a member of the AAA protein family, plays a crucial role in ribosome maturation. MDN1 is expressed in the human brain throughout life, especially during early development and adulthood. However, MDN1 variants have not been previously reported in patients with epilepsy. This study aims to explore the association between MDN1 variants and epilepsy.

Trios-based whole-exome sequencing was performed in a cohort of patients with epilepsy susceptibility from the China Epilepsy Gene 1.0 Project. The excess, damaging effects, and molecular subregional implications of variants, as well as the spatio-temporal expression of MDN1, were analyzed to validate the gene-disease association.

Compound heterozygous variants in MDN1 were identified in five unrelated patients with febrile seizures or secondary epilepsy. Three patients presented with febrile seizures/epilepsy with febrile seizures plus, while two patients developed epilepsy secondary to brain damage (five or seven years after). These variants were either absent or present at low frequencies in the control group, and exhibited statistically significant higher frequencies in the case group compared to controls. All the missense variants were predicted to be damaging by at least one in silico tool. In each pair of compound heterozygous variants, one allele was located in the AAA2-AAA3 domains, while the other allele was located in the linker domain or its vicinity. In contrast, most of the variants from the asymptomatic control group were located outside the AAA domains, suggesting a molecular subregional implication of the MDN1 variants.

MDN1 is potentially a susceptibility gene for epilepsy.

Aortic dissection (AD) is a lethal disease with a rising incidence and few effective preventive measures. This study investigated the therapeutic efficacy of puerarin (Pue) in attenuating AD, with a focused on elucidating its molecular mechanisms through NLRP3 inflammasome and matrix metalloproteinase-9 (MMP-9) modulation. In ApoE-deficient mice, AD mouse model was induced through a 5-week high-fat diet (HFD) feeding regimen followed by a 4-week subcutaneous infusion of angiotensin II (Ang II) via osmotic minipumps (1000 ng/kg/min). Our findings demonstrated that Pue intervention significantly reduced AD incidence and mortality. Furthermore, Pue alleviated hemodynamic stress through systolic blood pressure reduction and restored lipid homeostasis, as evidenced by decreased atherogenic lipids (TG, TC, LDL-C), elevated HDL-C levels, and attenuated aortic lipid deposition. Histopathological analyses revealed Pue preserved aortic integrity via suppression of medial extracellular matrix degradation, collagen disorganization, and elastic fiber fragmentation. Mechanistically, Pue inhibited NLRP3 inflammasome activation, downregulating NLRP3, caspase-1, ASC, and IL-1β expression at both mRNA and protein levels. Concurrently, Pue attenuated the expressions of MMP-9, MMP-2, COL1A1 and COL3A1, which was correlated with reduced co-localization of NLRP3/MMP-9 and CD68/IL-1β in immunofluorescence assays. RNA-seq and WGCNA analyses identified enriched inflammation-related pathways in AD tissues, with Pue reversing NLRP3-associated gene clusters. These findings established Pue as a multi-target phytotherapeutic agent that suppressed AD progression through dual inhibition of the NLRP3 inflammasome activation and MMP-9-mediated extracellular matrix remodeling, offering a promising adjunctive strategy for AD prevention.

Objective:To explore the clinical manifestations of IgG4-related diseases（IgG4-RD） complicated with moderately differentiated adenosquamous carcinoma of the parotid gland, the diagnostic criteria for IgG4-related diseases and parotid malignant tumors, treatment regimens, and the application of fine-needle aspiration in disease diagnosis, so as to reduce clinical misdiagnosis and missed diagnosis. Methods:A retrospective analysis was conducted on the case data of a patient with IgG4-related diseases（IgG4-RD） complicated with moderately differentiated adenosquamous carcinoma of the parotid gland admitted to our department in March 2024. The clinical characteristics, imaging findings, preoperative puncture results, and postoperative pathological features were analyzed, and relevant literatures on both diseases were reviewed and summarized. Results:The elderly male patient was admitted due to "a mass in the parotid area in front of the right ear for more than 3 months". Through clinical examination, imaging examination, laboratory examination, and preoperative needle biopsy, the diagnosis of "right parotid moderately differentiated adenosquamous carcinoma complicated with IgG4-related disease" was considered. It was also considered that IgG4-related disease did not involve other organs before surgery, so no systemic hormone therapy was given before or after surgery. After surgery combined with postoperative radiotherapy, follow-up showed that neither the parotid tumor nor IgG4-related disease recurred. Conclusion:"IgG4-related disease complicated with moderately differentiated adenosquamous carcinoma"is a rare clinical disease. Both lack typical clinical manifestations and specific imaging features, and the diagnosis is mostly unclear before surgery. Pathological examination is of great significance in the diagnosis of the disease, while fine-needle aspiration has limited value in the diagnosis, which should attract the attention of clinicians. In addition, for patients with both diseases, individualized treatment plans should be formulated.